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Discovery of a novel DYRK1A inhibitor with neuroprotective activity by virtual screening and in vitro biological
Xinxin Si1, Chenliang Qian1,2, Nianzhuang Qiu3
1School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, Jiangsu, China.
Abstract:
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is implicated in accumulation of amyloid β-protein (Aβ) and phosphorylation of Tau proteins, and thus represents an important therapeutic target for neurodegenerative diseases. Though many DYRK1A inhibitors have been discovered, there is still no marketed drug targeting DYRK1A. This is partly due to the lack of effective and safe chemotypes. Therefore, it is still necessary to identify new classes of DYRK1A inhibitors. By performing virtual screening with the workflow mainly composed of pharmacophore modeling and molecular docking as well as the following DYRK1A inhibition assay, we identified compound L9, ((Z)-1-(((5-phenyl-1H-pyrazol-4-yl)methylene)-amino)-1H-tetrazol-5-amine), as a moderately active DYRK1A inhibitor (IC50: 1.67 μM). This compound was structurally different from the known DYRK1A inhibitors, showed a unique binding mode to DYRK1A. Furthermore, compound L9 showed neuroprotective activity against okadaic acid (OA)-induced injury in the human neuroblastoma cell line SH-SY5Y by regulating the expression of Aβ and phosphorylation of Tau protein. This compound was neither toxic to the SH-SY5Y cells nor to the human normal liver cell line HL-7702 (IC50: >100 μM). In conclusion, we have identified a novel DYRK1A inhibitor with neuroprotective activity through virtual screening and in vitro biological evaluation, which holds the promise for further study.
Insights
Researchers discovered a novel Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitor, compound L9, with potential for treating neurodegenerative diseases. This safe and effective compound shows neuroprotective effects by modulating key disease proteins.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a therapeutic target for neurodegenerative diseases due to its role in amyloid β-protein (Aβ) accumulation and Tau protein phosphorylation.
- Existing DYRK1A inhibitors lack effective and safe chemotypes, necessitating the discovery of novel drug classes.
Purpose of the Study:
- To identify novel classes of DYRK1A inhibitors with potential therapeutic applications for neurodegenerative diseases.
- To evaluate the neuroprotective activity and safety profile of newly identified DYRK1A inhibitors.
Main Methods:
- Virtual screening, including pharmacophore modeling and molecular docking, was employed to identify potential DYRK1A inhibitors.
- In vitro DYRK1A inhibition assays were performed to determine the activity of identified compounds.
- Neuroprotective effects were assessed in a human neuroblastoma cell line (SH-SY5Y) against okadaic acid-induced injury.
- Cytotoxicity was evaluated in both SH-SY5Y and human normal liver cell lines (HL-7702).
Main Results:
- Compound L9, ((Z)-1-(((5-phenyl-1H-pyrazol-4-yl)methylene)-amino)-1H-tetrazol-5-amine), was identified as a moderately active DYRK1A inhibitor (IC50: 1.67 μM).
- Compound L9 exhibits a unique binding mode and structural difference from known DYRK1A inhibitors.
- L9 demonstrated significant neuroprotective activity by regulating Aβ and Tau phosphorylation in SH-SY5Y cells.
- L9 showed no toxicity to SH-SY5Y cells or HL-7702 cells (IC50: >100 μM).
Conclusions:
- A novel DYRK1A inhibitor, compound L9, was successfully identified through virtual screening and in vitro evaluation.
- Compound L9 possesses significant neuroprotective properties and a favorable safety profile, making it a promising candidate for further investigation in neurodegenerative disease therapeutics.
